CD4 T cells are an essential component of the immune responses against HIV and other viruses, but CD4 T cells are the prime targets for HIV infection. Hence, there are concerns that HIV vaccines which stimulate and expand CD4 T cells may supply more target cells for the virus and increase the host susceptibility to HIV infection. Nevertheless, in the course of HIV infection, not all antigen-specific CD4 T cells succumb to HIV and become infected. Antigen stimulation of CD4 T cells specific for certain HIV epitopes have been shown to render these cells more resistant to CCR5-tropic HIV and this resistance is associated with production of CCR5 ligands, i.e. CC chemokines MIP-1a, MIP-1[unreadable], and RANTES by the cells. While CC chemokine expression has been associated with Th1 responses, not all Th1 cells secrete these chemokines in response to their specific antigens. CD4 Th1 cells invariably display differential expression of MIP-1[unreadable] vs. other Th1 cytokines such as IFN-?, IL-2, and TNF- a, and the overall profiles of chemokines and cytokines produced by the responding T cells vary depending on the antigens used for stimulation. Many factors may account for and they are not fully understood. In this proposal we focus to evaluate one factor, i.e.. We hypothesize that To test these hypotheses, we will define a panel of helper epitopes from HIV-1 envelope (Env) gp120 and gp41 antigens and characterize them in terms of their ability to stimulate CD4 T cells to express different sets of cytokines and CC chemokines (Aim 1). We will then evaluate if CCR5 ligand secretion by CD4 T cells responding to their Env epitopes is specifically associated with increased resistance against in vitro HIV challenge and if CCR5 ligand-expressing CD4 T cells are indeed selectively protected and preserved in vivo during active chronic HIV infection (Aim 2). We also propose to evaluate parameters that can modulate the capacity of the different Env epitopes to elicit the distinct sets of cytokines and chemokines, including epitope concentrations, relative affinities of the epitope-HLA class II complexes, and amino acid substitutions within the epitopes (Aim 3). Finally, we plan to use the different Env epitopes to prime in vitro naive CD4 T cells from healthy uninfected subjects and determine if these epitopes also stimulate the primed CD4 T cells to produce distinct sets of cytokines and chemokines and if the primed CD4 T cells producing CCR5 ligands are more resistant to HIV challenge (Aim 4). The use of selective helper epitopes that preferentially elicit virus-specific CD4 T cells to produce CCR5 ligands and other cytokines necessary for B cell or CD8 T cell help, is one potential strategy for inducing potent anti-HIV immunity that also protects the CD4 T cells against the virus. A prophylactic HIV vaccine is the only feasible tool for combating the global pandemic of HIV and AIDS, but the candidate vaccines that have been tested in the clinical and preclinical trials in the past two decades have not been proven to be effective. This proposal aims to harness the capacity of CD4 T cells to produce CC chemokines with potent anti-HIV activities so that these cells can be protected from HIV, while performing their critical functions to help other immune cells. Data from this study will provide information about the types of CD4 T cell responses need for protection against HIV and thus should be directly applicable to the development of the much needed HIV vaccines.